Introduction
Environmental deterioration has increased hypertension prevalence [10]. Its adverse consequences involve structural and functional target-organ changes from additive external and internal environmental factors [13]. Cardiovascular remodelling begins early [7]. Left ventricular hypertrophy is the principal cardiac maladaptation to increased haemodynamic load and chronic neurohumoral activation [15]. Initially, nitric oxide (NO), the main vasodilator, prevents hypertrophy by unloading the heart and vessels [9]. Morphological changes reflect prolonged sympathetic and renin–aldosterone activation, growth factors and inflammatory cytokines, exhausted antioxidant defence, pulsatile NO production, interstitial fibrosis [16] and Fas-dependent cardiomyocyte apoptosis [8]. Impaired NO metabolism accelerates cardiovascular remodelling [2].
Under hypertension-associated oxidative stress, cytokine-induced NO acts not as a vasodilator but as a cytotoxic molecule promoting cytokine release, fibrosis and cardiomyocyte apoptosis [3]. Treatment should therefore stabilise haemodynamics, improve NO metabolism and influence myocardial remodelling [5].
Few clinical studies address correlations between impaired NO synthesis and left ventricular hypertrophy. Even successful antihypertensive treatment does not always cause hypertrophy regression [20].
Reduced adaptive reserves arise from depressed metabolic and energy processes due to chronic bioenergetic hypoxia [4], an additional adverse internal factor suppressing ecophysiological adaptation in hypertension [1]. Intermittent normobaric hypoxic therapy [11], the Mountain Air method, increases resistance to diverse internal and external pathogenic factors through hypoxia training. It is an effective non-drug treatment and prevention method for many diseases. Breathing a low-oxygen mixture produces hypoxia dosed by depth and duration. Unlike mountain exposure, normal atmospheric pressure is maintained, and the method combines with conventional medicine. Its broad action trains oxygen-deficiency tolerance and recruits reserves inherited from millions of years ago when atmospheric oxygen was minimal [12].
The objective was to determine NO’s role in myocardial morphological and functional restructuring and how intermittent normobaric hypoxic therapy influences NO metabolism and myocardial remodelling.
Materials and methods
Twenty outpatients with grade II hypertension, six men and fourteen women aged 60–80, mean 68.3±1.6 years, were enrolled. Hypertension duration averaged 18.5±2.1 years. Six also had CAD with class I–II exertional angina; four had myocardial infarction several years earlier; four had moderate asthma and two moderate type 2 diabetes. Exclusions were myocardial infarction or stroke within 1.5 years, severe arrhythmia or hepatic or renal dysfunction, decompensated chronic heart failure, mental illness, COPD exacerbation and alcohol or drug dependence. Patients were divided into two groups of ten. Group 1, controls, received baseline treatment only.
The ten experimental group 2 patients also received intermittent normobaric hypoxic therapy courses using Vershina hypoxicators designed for home use. Exposure duration was individualised using the Stange breath-hold test; the resulting breathing cycle lasted thirty minutes [11]. Breathing followed a cyclic fractionated pattern. Echocardiographic structural and haemodynamic cardiac characteristics were assessed before and nine months after the study [6]. Exhaled breath condensate NO metabolites, NO2 and NO3, were measured with Griess reagent on a Shumadzu spectrophotometer at 520 nm before the study and every three months throughout follow-up.
Results and discussion
All patients completed the study. No adverse psychoemotional or somatic reactions occurred during hypoxic therapy. Echocardiographic parameters before and after the study are shown in the table.
Before the study, group 1 had increased left ventricular mass, posterior-wall and septal thickness in systole and diastole, left atrial and right ventricular size and anteroposterior heart dimension, with reduced stroke volume and ejection fraction. Subsequently, ejection fraction and stroke volume declined markedly; end-systolic, end-diastolic and right ventricular dimensions increased, along with further left ventricular mass growth and significant increases in left atrial size, septal and posterior-wall thickness in both phases, and anteroposterior heart dimension.
Group 2 initially had reduced stroke volume and ejection fraction, increased septal thickness in both phases and anteroposterior dimension, and substantially increased posterior-wall thickness and left ventricular mass. Afterward, end-diastolic dimension, left ventricular mass, diastolic septal thickness, posterior-wall thickness in both phases and anteroposterior dimension decreased. Stroke volume and ejection fraction increased to normal; left atrial and right ventricular sizes were unchanged. Higher ejection fraction and lower end-systolic dimension indicate better systolic function [14]. Left ventricular morphometry and function therefore improved after hypoxic therapy.
Exhaled-condensate NO metabolites were initially elevated in both groups: 28.27±0.77 nM/mL in group 1 and 32.48±1.3 nM/mL in group 2. They remained high in controls afterward, 30.15±0.83 nM/mL. Additional hypoxic therapy normalised group 2 values to 24.26±0.96 nM/mL.
Progressing hypertrophy in group 1 accompanied high exhaled NO metabolites, possibly reflecting strained vasodilator mechanisms and uneven endogenous NO production against overall deficiency. Elevated metabolites correlated with greater left ventricular mass and posterior-wall and septal thickness, consistent with literature [9] and supporting endothelial dysfunction as a pathogenetic factor in hypertensive remodelling.
Initially, left ventricular hypertrophy is a physiological response to afterload from increased systemic resistance. Progression creates a mismatch between rising myocardial oxygen demand and limited coronary delivery. Hypoxia, oxidative stress and altered NO metabolism are major internal cardiodepressant factors limiting relaxation and accelerating fibrosis. Exhausted adaptive reserves manifest as lower ejection fraction and increased end-systolic and end-diastolic dimensions, which determine cardiac reserve and exercise tolerance [16].
Most drugs do not reverse fibrosis [17]; hypertension with hypertrophy therefore requires combined therapy addressing both normal blood pressure and improved adaptive capacity of myocardium and vessels. Adding hypoxic therapy improved NO metabolism in group 2. Intermittent normobaric hypoxic therapy is thus an appropriate clinical method with a cardiovascular training effect.
Some studies establish the pathogenetic importance of altered NO metabolism in hypertensive remodelling [19]. Basal NO supports endothelium-dependent vasodilatation and lower peripheral resistance, preventing hypertrophy through haemodynamic unloading and reduced arterial tone. Its role extends further: antiproliferative effects are reported [18]. Molecular mechanisms of excessive NO-induced contractile impairment and remodelling remain unclear. These findings further support NO metabolism disturbances as pathogenetically important in hypertensive myocardial remodelling.
Conclusions
Hypertension involves disturbed NO metabolism. NO-system changes cause structural and functional abnormalities and reduced myocardial contractility. Courses of intermittent normobaric hypoxic therapy improve cardiac contraction, slow remodelling and improve NO metabolism. This reliable, effective and accessible means of increasing ecophysiological reserves can be used in hypertension treatment.
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Full main-text translation of: Жеребкер Е.М., Чижов А.Я. Прерывистая нормобарическая гипокситерапия в лечении артериальной гипертонии. Клиническая геронтология. 2008;3:44–47.
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